As the COVID-19 global pandemic rages on, clinicians and politicians alike have responded enthusiastically to the potential for using known, already-approved drugs as treatments for SARS-CoV-2 infection. With no therapies yet approved by the FDA specifically for COVID-19, “repurposed” drugs may seem like a no-brainer.

Drug repurposing is not without risks, however. A compound approved as safe and effective for one indication many be neither effective nor safe for another. Weighing the potential benefits and risks of treatments is an integral part of the FDA approval process — one the agency takes very seriously. Even in the face of a global viral outbreak, the FDA has been unwilling to lower its standards lest it flout its chief responsibility: protecting the public health.

Accessing potential treatments during a public health emergency

Repurposing approved drugs for new indications may indeed be “an efficient drug development pathway for treatments for diseases and conditions that have few or no therapeutic options,” the FDA has said. The agency co-sponsored a two-day public meeting in December 2019 to explore repurposing possibilities [FDA Workshop Bulletin: Addressing Obstacles to Repurposing Off-Patent Drugs, 05/06-December-2019].

FDA speakers at the workshop explained the typical regulatory pathways for pursuing FDA approval of new drug applications (NDAs), biologics license applications (BLAs), and supplemental approvals to approved NDAs and BLAs. For repurposed drugs, the “intermediate pathway” described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) is likely the most relevant, they said — because it allows sponsors to pursue approval without conducting studies that would merely replicate what was already established about the product (i.e., in other clinical trials). A 505(b)(2) application typically relies on 1) prior findings of safety and effectiveness for a previously approved drug, and on 2) published literature.

Clearly, these are not “typical” times. However, even the FDA’s expedited approval programs are not designed to move products — even repurposed ones — to market fast enough to treat people already infected with SARS-CoV-2. However, there are existing FDA programs that could help speed the approval of products to treat COVID-19.

The ‘intermediate pathway’ described in section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) is likely the most relevant means of expending ‘drug repurposing’ approvals.

Emergency use authorization (EUA)—Section 564 of the FD&C Act describes EUA authorities that allow the FDA to facilitate the availability and use of medical countermeasures (MCMs) to strengthen public health protections against chemical, biological, radiological, and nuclear (CBRN) threats. Under that section, the FDA can authorize the use of unapproved medical products, or unapproved uses of approved products, if the secretary of the US Department of Health and Human Services (HHS) has declared an “emergency or threat” that justifies emergency use to diagnose, treat, or prevent serious or life-threatening disease/conditions caused by CBRN threats. In the case of COVID-19:

On January 31, 2020, the HHS secretary made a formal determination that a public health emergency exists in the US “as a result of confirmed cases of 2019 Novel Coronavirus (2019-nCoV).” As the FDA noted, however, this declaration did not enable the FDA to issue EUAs. For FDA action, the secretary had to make a separate determination and declaration under section 564 of the FD&C Act.

On March 10, in a declaration made under the Public Readiness and Emergency Preparedness Act (PREP Act), the HHS secretary extended “liability immunity” (effective February 4, 2020) to those who “manufacture, distribute, administer, prescribe or use” covered countermeasures. The declaration defines “covered countermeasure” as “any antiviral, any other drug, any biologic, any diagnostic, any other device, or any vaccine, used to treat, diagnose, cure, prevent, or mitigate COVID-19, or the transmission of SARS-CoV-2 or a virus mutating therefrom, or any device used in the administration of any such product, and all components and constituent materials of any such product.”

On March 24, the secretary declared that circumstances justify authorizing the emergency use of medical devices during the pandemic, including “alternative products used as medical devices,” as well as ventilators, anesthesia gas machines modified for use as ventilators, ventilator tubing connectors, and other accessories.

The FDA has already issued EUAs for multiple COVID-19 diagnostic tests, and laboratories and manufacturing companies nationwide are working to develop and distribute others [FDA Workshop Bulletin: FDA Policy for COVID-19 Diagnostic Tests, 25-March-2020]. (Note: The FDA makes online updates to its list of EUA authorizations for COVID-19 diagnostics.) The agency has also issued EUAs for disposable filtering facepiece respirators (FFRs) approved by the National Institute for Occupational Safety and Health (NIOSH) and for “certain” imported FFRs that are not NIOSH-approved.

Expanded access

Commonly called “compassionate use,” the FDA’s expanded access program enables access to investigational new drugs (INDs) outside of clinical trials and to approved drugs when their availability is limited by a risk evaluation and mitigation strategy (REMS). As explained in 21 CFR 312, Subpart I, expanded access is intended to “facilitate the availability of such drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or condition.”

The criteria for expanded access includes a requirement that “potential patient benefit justifies the potential risks of the treatment use,” and that potential risks “are not unreasonable” vis-à-vis the disease or condition. Additionally, expanded access to the drug must not interfere with clinical investigations “that could support” approval of the drug for the same use. The FDA can grant expanded access to individual patients or to groups of patients, although specific criteria must be met for individual patients (including for emergency use), for “intermediate-size” patient populations, and for widespread treatment use.

Current efforts

One of the treatments currently under investigation for COVID-19 is convalescent plasma, described by the FDA as “antibody-rich blood products that are taken from blood donated by people who have recovered from the COVID-19 virus, that could shorten the length, or lessen the severity, of the illness” [FDA Press Release, 24-March-2020]. The agency website “encouraged” researchers interested in convalescent plasma to submit requests for its investigational use, citing the “traditional” IND regulatory pathway found at 21 CFR 312.

Individual patients “with serious or immediately life-threatening COVID-19 infections” can seek expanded access to COVID-19 convalescent plasma if their physicians apply for a single-patient emergency IND (eIND), the FDA website states. As explained in 21 CFR 312.310, this type of expanded access pertains to “the treatment of an individual patient by a licensed physician.”

On the repurposing front, researchers at The Scripps Research Institute are reviewing the >14,000 compounds in ReFRAME, a collection of FDA-approved drugs, to identify existing antivirals that could be effective treatments for people exposed to SARS-CoV-2. Other Scripps Research projects are assessing molecules that could keep SARS-CoV-2 from replicating, and investigating the use of existing drugs as add-ons to improve the effectiveness of remdesivir (by Gilead Sciences, Inc), a drug under investigation in six COVID-19 clinical trials.

As the pandemic proceeds, companies developing drugs to treat COVID-19 face increasing demand for their investigational products. Gilead’s website refers to “overwhelming demand” for remdesivir, for example, and states that the company “is currently in the process of transitioning” from accepting individual compassionate use requests for the drug to developing a program for broader use.

Lessons learned

The dangers of taking a hasty approach to drug repurposing were dramatically illustrated this week, when an Arizona man died after ingesting chloroquine phosphate, a chemical he apparently thought would protect him from SARS-CoV-2 infection.

Medical chloroquine is a prescription-only drug, first approved by the FDA in 1949 as an antimalarial. But another, non-medical form of chloroquine is found in products used to clean fish tanks. According to news accounts, the man and his wife both consumed the chemical after seeing televised reports extolling its promise as a potential treatment for COVID-19.

Rarely a good idea, self-medicating can be deadly when clinical trial data are lacking about a product’s use in a particular indication. Even the most trusted sources may not fully understand the risks.

“The nice part is that it’s been around a long time,” U.S. president Donald Trump said about chloroquine at a White House press conference on March 19, “so we know that if—if things don’t go as planned, it’s not going to kill anybody.”

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